Acidification of extracellular space occurs in brain ischemia. This acidification is one important contributor to ischemia-induced neuronal injury. Current literature emphasizes an injurious role of acidosis, mediated mostly by the acid-sensing ion channels in ischemia. The current proposal investigates a novel signaling pathway mediated by ovarian cancer G protein-coupled receptor 1 (OGR1), an acid-sensitive G protein coupled receptor. With the OGR1 null mice and organotypic hippocampal slices, we will test the hypothesis that activating the OGR1 pathway attenuates acidosis- and ischemic-induced neuronal injury. The proposed research will uncover an unexpected neuroprotective aspect of acidosis. The results will reveal a biphasic (pro-survival vs. pro-injury) picture of acidosis in neuronal survival, and will be critical for future therapeutic interventions in stroke and other neurological diseases that reduces brain pH.